Wilson Disease – Symptoms, Diagnosis And Treatment

Wilson disease is a rare inherited disorder in which excessive amounts of copper accumulate in the body, particularly in the liver, brain, and eyes.

It is also called hepatolenticular degeneration syndrome or copper storage disease.

Most people present with symptoms between 5 to 35 years of age, but it can affect younger and older people, as well.

It is a rare disease that affects approximately 1 in 30,000 individuals.

The clinical features include a combination of liver disease, neurological and neuropsychiatric problems. In the absence of treatment, Wilson disease can cause liver failure, severe brain damage, and even death.

When diagnosed early, before serious organ damage occurs, Wilson’s disease is treatable, and many people lead normal lives.

Cause and Pathophysiology

Copper is a trace mineral that is required by the body for the development of nerves, bones, collagen, and melanin (the skin pigment). It is required by the body in small amounts and is obtained from the food we eat. The excess copper is excreted through the liver into the bile.

In people with Wilson’s disease, there is a genetic defect caused by mutations in the ATP7B gene. This gene provides instructions for the formation of copper transporting protein. Due to the deficiency of this protein, the liver does not release copper into bile. This leads to the accumulation of copper in the body.

Copper begins to build up in the liver immediately after birth and ultimately damages the liver. Once the liver is unable to hold the excess copper, it is released into the bloodstream. It then travels and gets deposited in other organs ultimately causing their damage.

This condition is inherited in an autosomal recessive pattern which means that a person must have inherited two separate genes, one from their mother and one from their father to have the condition. If a person only inherits one defective gene they are said to be a carrier, and do not have the condition itself, but possess the ability to pass it onto their offspring.

Diagnosis

Early diagnosis is important for stopping the progression of Wilson’s disease. Because it is a relatively rare disease, signs and symptoms of liver disease or neuropsychiatric symptoms may initially be attributed to other causes.

Physical examination

General examination

Look for hepatomegaly or splenomegaly

Checking eyes under a bright light (slit-lamp examination) by an ophthalmologist for Kayser-Fleischer rings or sunflower cataracts

Liver Function Tests

Ceruloplasmin level

In Wilson’s disease, lower levels of ceruloplasmin are found (< 20 mg/dl)

The normal range for ceruloplasmin in the blood is between 20 to 50 mg/dl.

24-hour urinary excretion of copper

Total urine produced in 24 hours is collected in a bottle free of copper and then the level of copper in this urine is estimated. Levels > 100 μg/24 hours confirm the diagnosis of Wilson disease while levels > 40 μg/24 hours are strongly indicative of the disease.

Copper level

Raised serum free copper level (non–ceruloplasmin-bound) >25 μg/dL

The total serum copper is made up of ceruloplasmin-bound copper and free copper. The ceruloplasmin and the ceruloplasmin-bound copper levels are typically low in Wilson Disease. This explains the overall reduction in total serum copper concentration. However, the free (i.e., non–ceruloplasmin-bound) copper is usually found to be elevated.

Liver biopsy

A tiny piece of the liver is taken after passing a fine hollow needle through the skin into the liver. This small liver sample is then studied under a microscope. It is done for the following purposes

To assess the severity of liver damage or cirrhosis

For chemical analysis of the copper concentration in the tissue sample. This is a standard test for the diagnosis of Wilson disease. Copper levels > 250 μg /g of dry weight are diagnostic of Wilson disease even in asymptomatic patients.

Genetic testing

It is done to detect the gene mutation. Genetic testing is also recommended for all first-degree relatives of a person diagnosed with Wilson disease to see if they are a carrier or could have the disease. It can help parents determine the potential risk of passing this disease to their offspring.

These may help show any brain abnormalities or liver damage. These investigations can’t diagnose the disease, but they can help determine the extent or severity of the disease.

A practical approach to diagnosis

The presence of Kayser-Fleischer rings, low ceruloplasmin levels (< 20 mg/dL) and the presence of neurological symptoms are suggestive of the diagnosis of Wilson disease.

If a patient shows only liver disease, the presence of a liver copper concentration of more than 250 μg/g of dry weight and a low serum ceruloplasmin level (< 20 mg/dL) are used to confirm the diagnosis.

Thus, in the absence of Kayser-Fleischer rings or neurologic symptoms, a liver biopsy for the quantitative determination of copper is necessary to establish the diagnosis of Wilson disease.

Treatment

Treatment involves 3 stages and should continue throughout life. If treatment is delayed or stopped, copper can again build-up in the organs.

First stage

The first part of the treatment involves removing excess copper from the body. This is done through chelating agents that remove the extra copper from the organs and release it into the bloodstream. The kidneys then filter this copper into the urine.

Commonly used chelating agents include drugs like d-penicillamine (Cuprimine, Depen) and trientine (Syprine).

D-penicillamine can cause serious side effects, including skin rashes, kidney problems, bone marrow suppression, and worsening of neurological symptoms. It also increases the urinary excretion of vitamin B-6 (pyridoxine), so vitamin B-6 supplements should be taken along with this treatment.

Trientine produces lesser side effects than penicillamine. Still, it can cause worsening of neurological symptoms

Second stage or Maintenance therapy

Once the excess copper is removed from the body, the next step is to maintain the normal level of copper. The commonly used drug is zinc acetate (Galzin).

This drug prevents the body from absorbing copper from the foods eaten.

Zinc may be used as first stage treatment if a person can’t take chelating agents. Zinc can cause stomach upset.

Third stage

Once the copper levels return to normal and the symptoms improve, the next part of treatment involves long-term maintenance therapy.

This includes

Continuing chelating therapy or zinc.

Regularly monitoring the copper levels in the body.

Lifestyle and home remedies

Dietary changes: Foods containing a high level of copper should be avoided. These include:

dried fruit

nuts

mushrooms

liver

shellfish

chocolate

multivitamins containing copper Liver

The copper content of the water at home should be checked. If the home has copper pipes, there may be excess copper present in the water.

Liver transplant

The diseased liver is removed and replaced with a healthy liver from a donor. It is done in the following cases:

Non-responsive to treatment

In case of severe liver damage

If successful, a liver transplant results in curing Wilson disease. The success rate for liver transplants is 85 percent after one year.

Long-term Outlook

The sooner the diagnosis of Wilson disease is made, the better is the long term outlook or prognosis. If left untreated, Wilson disease can result in liver failure and brain damage.

Early treatment can prevent neurological and liver damage and can even reverse the damage. If treated in later stages, the progression of the disease can be stopped but the damage which has already occurred can’t be reversed.

Since Wilson disease is an inherited condition, nothing can be done to prevent it. One can, however, prevent or delay the onset of symptoms and the complications.

Future Options

In the future, treatments like hepatocyte transplantation and gene therapy may revolutionize the treatment of Wilson disease. Although both these treatments have shown promising results in animals, definite human studies are needed to establish their long-term usefulness and ability to replace medical treatment and liver transplantation.